Blockade of Motor Cortical Long-Term Potentiation Induction by Glutamatergic Dysfunction Causes Abnormal Neurobehavior in an Experimental Subarachnoid Hemorrhage Model

Abstract

Subarachnoid hemorrhage (SAH) is a life-threatening condition that can also lead to permanent paralysis. However, the mechanisms that underlying neurobehavioral deficits after SAH have not been fully elucidated. As theta burst stimulation (TBS) can induce long-term potentiation (LTP) in the motor cortex, we tested its potential as a functional evaluation tool after experimentally induced SAH. Motor cortical inter-neuronal excitability was evaluated in anesthetized rats after 200 Hz-quadripulse TBS (QTS5), 200 Hz-quadripulse stimulation (QPS5), and 400 Hz-octapulse stimulation (OPS2.5). Furthermore, correlation between motor cortical LTP and N-methyl-D-aspartate-receptor activation was evaluated using MK-801, a NMDA-receptor antagonist. We evaluated inhibition-facilitation configurations [interstimulus interval: 3 ms; short-latency intracortical inhibition (SICI) and 11 ms; intracortical facilitation (ICF)] with paired electrical stimulation protocols and the effect of TBS paradigm on continuous recording of motor-evoked potentials (MEPs) for quantitative parameters. SAH and MK-801 completely blocked ICF, while SICI was preserved. QTS5, QPS5, and OPS2.5 facilitated continuous MEPs, persisting for 180 min. Both SAH and MK-801 completely blocked MEP facilitations after QPS5 and OPS2.5, while MEP facilitations after QTS5 were preserved. Significant correlations were found among neurological scores and 3 ms-SICI rates, 11 ms-ICF rates, and MEP facilitation rates after 200 Hz-QTS5, 7 days after SAH (R2 = 0.6236; r = −0.79, R2 = 0.6053; r = −0.77 and R2 = 0.9071; r = 0.95, p < 0.05, respectively). Although these findings need to be verified in humans, our study demonstrates that the neurophysiological parameters 3 ms-SICI, 11 ms-ICF, and 200 Hz-QTS5-MEPs may be useful surrogate quantitative biomarkers for assessing inter-neuronal function after SAH.

Monophasic-Quadripulse Theta Burst Magnetic Stimulation for Motor Palsy Functional Evaluation After Intracerebral Hemorrhage

“…For example, alterations in motor cortical interneuron excitability related to I1 or late I3 waves under such conditions result in the suppression or enhancement of the MEP response to single TMS ( Amassian et al, 1990 ; Di Lazzaro et al, 2003 , 2008 ). However, in contrast to surgical preoperative cases with severe paresis and consciousness disturbances, the present cases only exhibited targeted motor paresis with small volume, which was therefore favorable for motor function-oriented MEP studies ( Fujiki et al, 2021 ). Second, the relationship between electrophysiological parameters related to motor dysfunction after ICH and its morphological correlation with MRI data [such as diffusion tensor tractography, fractional anisotropy, or apparent diffusion coefficient; Kusano et al (2009) and Venkatasubramanian et al (2013) ] and the correlations between both modalities in long-term neuronal dysfunction remain unclear.…”

“…In this regard, the direct link between neurobehavioral features and electrophysiological, morphological, and molecular-level assessments to address safety issues, and 500-Hz high-frequency TBS and MEP amplification induction in the human brain, requires further careful and detailed studies. Indeed, QPS over long durations (up to 30 min) with monophasic high-frequency magnetic or electrical motor cortical stimulation in both humans ( Hamada et al, 2013 ; Shirota et al, 2017 ) and animals ( Müller-Dahlhaus and Vlachos, 2013 ; Fujiki et al, 2021 ) can induce long-term potentiation/depression and altered synaptic plasticity. A comparable stimulus potential with a shorter duration was possible with TBS.…”

“…QTS-MEP acquisitions were triggered from the end of the fourth-final burst to evaluate corticospinal function in patients with ICH ( Figure 2 ). For testing, trains of stimuli were delivered every 10 s (SP) to 110 s (QPS and QTS) to allow for response recovery ( Fujiki et al, 2021 ).…”

“…Motor evoked potential data were analyzed offline and assessed visually by a single experienced professional (MF), using Brain-Vision-Analyzer2 (Brain-Products, Munich, Germany), similar to previous reports ( Sykes et al, 2016 ; Fujiki et al, 2021 ). Latencies and peak-to-peak MEP amplitudes were measured (at 120% RMT-intensity, i.e., six-individual-sweeps in each-minute run).…”

“…Recently, it has been demonstrated that anterior-posterior (AP) directed continuous quadripulse theta burst magnetic stimulation (QTS) at 666 Hz, with a burst repetition rate of 5 Hz, using 90% active motor threshold-TMS to the hand area of the primary motor cortex, induced an AP-MEP amplitude increase lasting up to 60 min ( Jung et al, 2016 ). Due to the controversial methodological standardization of MEP amplification on the motor cortex either intraoperatively or in awake settings in both humans and animals ( Deletis and Sala, 2008 ; Deletis and Fernández-Conejero, 2016 ; Sykes et al, 2016 ; Ushio et al, 2018 ; Fujiki et al, 2021 ), a comparison between a facilitatory TBS protocol and standard MEP induction in both awake healthy controls and clinical conditions is needed. Therefore, we developed a monophasic magnetic QTS-induced MEP device system that includes a set of 16 separate magnetic stimulators (Magstim 2002; The Magstim Co. Ltd., Spring Gardens, Whitland, United Kingdom) connected with a specially designed combination module that combines outputs from the 16 stimulators to allow a train of 16 monophasic magnetic pulses to be delivered through a single coil in awake patients with motor deficits.…”